Dyslipidemia and atherosclerosis. A forecast of pharmaceutical approaches.
Five classes of lipid-lowering drugs are approved by the Food and Drug Administration (FDA) for use in the United States: nicotinic acid, bile acid sequestrants, fibric acid derivatives, reductase inhibitors, and probucol. None of the agents has an antiatherosclerotic indication. Cholestyramine and gemfibrozil have received indications for preventing complications of atherosclerosis, namely, myocardial infarction and coronary artery disease death. Foreseeable pharmacological strategies to reduce lipid-related cardiovascular risk might be divided into three categories. First, the present approach of lowering lipid and lipoprotein concentrations might be extended through modification of available agents (e.g., a more potent or soluble bile acid resin) or development of agents of novel mechanism (e.g., acyl-CoA:cholesterol acyltransferase [ACAT] inhibition or inhibition of cholesterol biosynthesis at a step other than HMG-CoA reductase). Second, blood lipids could be directly addressed outside of lipid-lowering strategies. Raising high density lipoprotein (HDL) cholesterol levels has not been fully explored, or the target might be modification of the lipoproteins themselves rather than their concentrations. Areas of particular interest in the latter regard are hepatic lipase activity, cholesteryl ester transfer protein activity, and differences between oxidized or otherwise modified low density lipoprotein (LDL) particles and normal LDL. Third, it may be possible to directly lessen the atherosclerotic potential of the vessel wall (e.g., through protecting it from the effects of certain growth factors or altering its state of relaxation.